Cyclic imides are useful as intermediates in the production of important organic molecules. For example, the Floxacin antibiotics, a widely used, commercially important family of synthetic compounds, can be synthesized from relatively inexpensive phthalic anhydrides by using phthalimides prepared according to the process of this invention.
Though the production of cyclic imides by the reaction of cyclic anhydrides with primary amines has been known for decades, the process has deficiencies in important areas. Despite the fact that the production of cyclic imides is an endeavor of commercial importance, the deficiencies have persisted.
For instance, a method from the literature for producing N-methyl tetrachlorophthalimide from tetrachlorophthalic anhydride is by the direct reaction of tetrachlorophthalic anhydride with methylarnine in an aprotic solvent at temperatures as high as 200.degree. C. Conditions are typically anhydrous due to the potential for the anhydride to hydrolyze and give rise to a dicarboxylic acid. The formation of the anhydride is a reaction which competes with the formation of the cyclic imide, thus diminishing yield and purity of the desired product.
The use of anhydrous conditions puts a severe limitation on the large scale production of many cyclic imides, as well as the use of many cyclic imides in stepwise industrial processes, for it necessitates the handling of solid and gaseous reactants. In general, the handling of solids and gases is significantly more costly and labor intensive than the handling of aqueous solutions. Thus, the utility of the cyclic imide formation reaction is encumbered by a constraint which limits its usefulness in organic synthesis, especially when carried out on an industrial scale. Furthermore, the use of anhydrous conditions is typically only a partial solution, for even under anhydrous conditions, other ring-opened impurities are often formed in significant amounts.
It has previously been demonstrated that the use of carboxylic acids as solvents in the cyclic imide formation reaction favors the formation of the cyclic imide as opposed to the formation of ring-opened impurities, thus improving both purity and yield. However, even when using carboxylic acid solvents, literature methods adhere to anhydrous conditions. In light of the fact that acidic conditions are known to exacerbate the tendency of anhydrides to undergo hydrolysis in the presence of water, it is not surprising that methods which utilize carboxylic acids to produce cyclic imides in high product purity and yield also maintain anhydrous conditions.
It would represent a significant advance in the state of the art if a method of preparing cyclic imides could be found which eliminates the handling problems associated with solids and gases while maintaining the excellent yield and purity produced in the presence of a carboxylic acid solvent.